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Talk by Markus Damme

Title: "Lysosomal dysfunction in dementia – a focus on TMEM106B"
Occasion: SFB Seminar
Start: 16.01.2025 4:15 pm
Location: CellNanOs, 38/201

About the speaker: Prof. Dr. Markus Damme conducts research at the Biochemical Institute, Christian-Albrechts-University, Kiel.

Genetic variants in TMEM106B, coding for an endo-/lysosomal type II transmembrane protein of unknown function, have been identified as critical genetic modulators in various neurodegenerative diseases with a particularly strong effect in patients with frontotemporal degeneration (FTLD. The luminal domain of TMEM106B can form amyloid-like fibrils upon proteolysis; however, if these fibrils are disease-modulating or causative is still unclear.

To understand the physiological function of TMEM106B and the formation of TMEM106B-fibrils, we generated and characterized TMEM106B in detail in recent years and knocked it out in mice, resulting in massive axonal LAMP1-positive vacuoles at the proximal axon initial segment of motorneurons, suggesting axonal trafficking defects of lysosomes particularly in the proximal axon. The mice develop late-onset neuronal degeneration with Purkinje cell death and gliosis.

A critical question is how fibrils are generated. We therefore performed a detailed study of how TMEM106B is modified by proteolysis. We developed a commercially available monoclonal antibody against the luminal domain of TMEM106B, which allowed a detailed survey of the biosynthesis and proteolytic processing under physiological conditions in cellular models and TMEM106B-related mouse models. Moreover, fibrillary TMEM106B was detected in primary human autopsy material. We found that the luminal domain is generated under physiologic conditions by multiple lysosomal cysteine-type proteases ("shedding"). Lysosomal cysteine-type proteases perform additional C-terminal trimming of the luminal domain, for which experimental evidence has been lacking so far.

The presented results allow an in-depth perception of the processing of TMEM106B, which is a prerequisite to understanding factors leading to fibril formation and initial insight into its physiological function in lysosomes.